The chemotactic cytokines, or chemokines, are a family of proteins, approximately 8-10 kDa in size that function, at least in part by modulating a complex and overlapping set of biological activities important for the movement of lymphoid cells and extravasation and tissue infiltration of leukocytes in response to inciting agents (see, for example: P. Ponath, Exp. Opin. Invest. Drugs, 7:1-18, 1998). The cellular receptors for these proteins are classified based on the chemokine natural ligand. Receptors of the β-chemokines are designated with the prefix “CCR” whereas the receptors of the α-chemokine are designated with the prefix “CXCR”. The natural chemokine ligand for the CXCR4 receptor is stromal cell-derived factor-1 (SDF-1).
The inhibition of the binding of SDF-1 to CXCR4 by specific small-molecule inhibitors has been shown, in a model, to reduce the severity of the pathogenesis of collagen II-induced arthritis (P. Matthys, S. Hatse, K. Vermiere, A. Wuyts, G. Bridger, G. W. Henson, E. De Clercq, A. Billiau and D. Schols, J. Immunol. 107: 4686-4692, 2001). This model, which is used as a study model for the pathogenesis of rheumatoid arthritis in humans, shows that SDF-1 plays a central role in the pathogenesis of murine collagen induced arthritis. Similarly, the use of small-molecule CXCR4 inhibitors has been shown, in a murine model, to reduce a number of pathological parameters related to asthmatic-type inflammation in an allergin-induced inflammation (N. W. Lukacs, A. Berlin, D. Schols, R. T. Skerlj, G. J. Bridger, Am. J. Pathology, 160 (4): 1353-1360, 2002).
Two specific chemokine receptors, CXCR4 and CCR5, have been implicated in the etiology of infection by human immunodeficiency virus (HIV). The T cell-line tropic (T-tropic) viral phenotype of HIV requires, for infection, an association with the CXCR4 receptor, which is expressed in the surface of certain cells of the immune system (Carroll et al., Science, 276: 274-276, 1997). Specifically, an interaction between HIV and the CXCR4 receptor is required for membrane fusion, a necessary step in the infection of the host immune cell.
The heterocyclic compounds disclosed in U.S. Pat. No. 5,583,131, U.S. Pat. No. 5,698,546 and U.S. Pat. No. 5,817,807 selectively bind to the CXCR4 receptor, inhibiting the binding of the natural SDF-1 ligand. Such binding may show anti-inflammatory effects. The binding also competitively prevents the binding of the T-tropic HIV with the receptor, and thus imparts a preventative effect against HIV infection.
The compound of Formula I, (S)-(N′-(1H-benzimidazol-2-ylmethyl)-N′-5,6,7,8-tetrahydroquinolin-8-yl-1,4-butanediamine, is disclosed and claimed along with salts, pro-drug forms, and stereoisomeric forms thereof in WO 03055876, the entire disclosure of which is incorporated herein by reference. Preferably among the pharmaceutically acceptable salts described in WO 03055876 and the only salt form prepared therein is the hydrobromide salt. The compound of the Formula I is intended to be used as an orally dosed pharmaceutical agent in the treatment of HIV infections, and the present salts of Formula I suffer from problems associated with hygroscopicity.

Citation of the above documents is not intended as an admission that any of the foregoing is pertinent prior art. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents. Further, all documents referred to throughout this application are incorporated in their entirety by reference herein.